Background: The study aimed to investigate the effectiveness of a single versus double dose of prostaglandin E2 “misoprostol, 400 microgram” prior to myomectomy for multiple uterine fibroids. Methods: This was a prospective randomized controlled trial comprised of 69 patients with multiple myomas undergoing myomectomy. Patients received either an intra-vaginal single dose of 400 microgram misoprostol 1 hr pre-operatively (group A, 34 cases) or 2 doses, 3 and 1 hr prior to surgery (group B, 35 cases). Operation time, intra and post-operative blood loss, hemoglobin concentration, blood pressure and body's temperature were estimated and compared in both groups. The data were statistically analyzed using chi-square test. The p<0.05 was considered significant. Results: In group B, the mean operative time was significantly (p<0.001) shorter than in group A (25.8±4.14 vs. 35.4±5.6 min respectively). The mean value for operative blood loss was significantly (p<0.001) smaller in group B (101.4±25.5 vs. 200.16±18.8 ml). There was a significant (p<0.01) rise of the body temperature in group B (38.5±0.7 vs. 37.18±0.84°C). There were no differences between the two groups regarding hemoglobin levels, post-operative febrile morbidity or length of hospital stay. Conclusion: In this study, two doses of pre-operative intra-vaginal misoprostol were more effective than one dose in reducing intra and post-operative blood loss and shortening of operation time during abdominal myomectomy.